The present invention is concerned with a series of new macrolide compounds. The new compounds have valuable acaricidal, insecticidal and anthelmintic activities which are generally referred to herein as parasiticidal activities. This invention also provides methods of preparing the novel macrolide compounds and parasiticidal compositions containing the compounds, and methods for using them.
The new compounds provided by this invention are macrolides chemically related to the known milbemycins, avermectins, and similar compounds. There are several classes of known compounds with a structure based on a 16-membered macrolide ring. They are obtained by fermentation of various microorganisms or semi-synthetically by chemical derivatization of such natural fermentation products, and exhibit acaricidal, insecticidal, anthelmintic and other antiparasitic activities. The milbemycins and avermectins are examples of two such classes of known compounds, but various other classes also exist and are identified by different names or code numbers. The names for these various macrolide compounds have generally been taken from the names or code numbers of the micro-organisms which produce the naturally occurring members of each class, and these names have then been extended to cover the chemical derivatives of the same class, with the result that there has been no standardized systematic nomenclature for general use with such compounds.
In order to avoid confusion, reference in this patent specification will be made to names based on the hypothetical parent compound represented by formula (A): ##STR2## For the avoidance of doubt, formula (A) also shows the numbering of some carbon atoms most relevant to the compounds of the present invention. The methyl group at the 4-position has been numbered C-26.
The naturally produced milbemycins form a series of compounds. Milbemycins A.sub.3 and A.sub.4, among others, were disclosed in U.S. Pat. No. 3,950,360, and milbemycin D was disclosed in U.S. Pat. No. 4,346,171, where it was referred to as "Compound B-41D". These compounds may be represented by the above formula (A) in which position 25 is substituted respectively with a methyl group, an ethyl group or an isopropyl group. The milbemycin analogue substituted at position 25 with a sec-butyl was disclosed in U.S. Pat. No. 4,173,571.
Various derivatives of the original milbemycins have been prepared and their activities have been investigated. For example, 5-esterified milbemycins have been disclosed in U.S. Pat. Nos. 4,201,861, 4,206,205, 4,173,571, 4,171,314, 4,203,976, 4,289,760, 4,457,920, 4,579,864 and 4,547,491; in European Patent Specifications 8184, 102,721, 115,930, 142,969, 180,539 and 184,989; and in Japanese Patent Applications Kokai 57-120589 and 59-16894.
13-Hydroxy-5-ketomilbemycin derivatives have been disclosed in U.S. Pat. No. 4,423,209. Milbemycin 5-oxime derivatives were disclosed in U.S. Pat. No. 4,547,520 and European Patent Specification 203,832. British Patent Specification 2,168,345 disclosed milbemycin derivatives having a carboxy or esterified carboxy substituent at position 13 in combination with a hydroxy or esterified hydroxy substituent at position 5.
Like the milbemycins, the avermectins are based upon the same 16-membered macrolide ring compound. The avermectins were disclosed, for example in J Antimicrob Agents Chemother, 1979, 15, 361 (1979) and J Am Chem Soc, 1981, 103, 4216. These compounds may be represented by the above formula (A) but with position 13 substituted with a 4'-(.alpha.-L-oleandrosyl)-.alpha.-L-oleandrosyloxy group. Position 25 may be substituted with an isopropyl group or a sec-butyl group, and either there is a carbon-carbon double bond between positions 22 and 23, or there is a hydroxy group at position 23.
The avermectins are defined as follows:
______________________________________ avermectin C.sub.22 -C.sub.23 R.sub.25 R.sub.23 R.sub.5 ______________________________________ A.sub.1 a db sec-Bu H OMe A.sub.1 b db i-Pr H OMe A.sub.2 a sb sec-Bu OH .sup. OMe A.sub.2 b sb i-Pr OH .sup. OMe B.sub.1 a db sec-Bu H OH B.sub.1 b db i-Pr H OH B.sub.2 a sb sec-Bu OH .sup. OH B.sub.2 b sb i-Pr OH .sup. OH ______________________________________
In the above table, R.sub.25 is a substituent at the 25 position; R.sub.23 is a substituent at the 23 position; and R.sub.5 is a substituent at the 5 position; "db" indicates a double bond between positions 22 and 23; and "sb" indicates a single bond between positions 22 and 23.
The 23-keto derivatives of avermectin A.sub.2 a, A.sub.2 b, B.sub.2 a and B.sub.2 b are known from U.S. Pat. No. 4,289,760. 22,23-Dihydroavermectins may be obtained by reduction of the double bond between the 22 and 23 positions and were disclosed in U.S. Pat. No. 4,199,569. The aglyclone derivatives of the avermectins, which are milbemycin analogues, have sometimes been referred to in the literature as C-076 compounds, and various derivatives are known. For example, U.S. Pat. No. 4,201,861 disclosed such derivatives substituted with a lower alkanoyl group at position 13.
European Patent Specification 74,758 disclosed avermectin compounds which are derivatized at the 4-methyl group. The conversion of the 4-methyl group to a hydroxymethyl group is described, along with the formation of various oxymethyl derivatives such as acetyloxymethyl, benzoyloxymethyl and other carbonyloxymethyl compounds.
European Patent Specification 170,006 disclosed a family of bioactive compounds produced by fermentation, identified collectively by the code number LL-F28249. Some of these have a 16-membered macrolide structure corresponding to the above formula (A), substituted with hydroxy at position 23 and with a 1-methyl-1-propenyl, 1-methyl-1-butenyl or 1,3-dimethyl-1-butenyl at position 25. In these compounds, the hydroxy at position 5 may also be replaced by methoxy.
The same or similar compounds identified as S-541 compounds are known from British Patent Specification 2,166,436. The 23-keto derivatives and 23-deoxy derivatives of S-541 are known from Belgian Patent 904,709. S-541 derivitives with a carbon-carbon double bond at positions 22 and 23 were disclosed in European Patent Specification 215,654. The 26-hydroxy and 26-C.sub.1-4 alkanoyloxy derivatives of S-541 and of the 23-keto and 23-deoxy derivatives of S-541 are known from European Patent Specification 237,341.
British Patent Specification 2,176,182 disclosed another group of macrolide antibiotics corresponding to the above formula (A), with a hydroxy or substituted hydroxy group at position 5, a hydroxy, substituted hydroxy or keto group at position 23, and an .alpha.-branched alkenyl group at position 25.
A yet further group of related macrolide derivatives was disclosed in Japanese Patent Application Kokai 62-29590. These have a structure corresponding to the above formula (A), with a hydroxy or methoxy group at position 5. Position 13 of the ring can be substituted with a 4'-(.alpha.-L-oleandrosyl)-.alpha.-L-oleandrosyloxy group, as in the avermectins, and there may be a carbon-carbon double bond between positions 22 and 23, or alternatively position 23 may be substituted with a hydroxy group. The substituent at position 25 is of a type not found in the naturally produced milbemycins and avermectins, and includes various .alpha.-branched alkyl, alkenyl, alkynyl, alkoxyalkyl, alkylthioalkyl and cycloalkylalkyl groups, or cycloalkyl, cycloalkenyl or heterocyclic groups. This 25-substituent is introduced by adding the corresponding carboxylic acid or derivative thereof to the fermentation broth of an avermectin-producing micro-organism.
The various classes of milbemycin-related macrolide compounds described above are all said to have one or more types of activity as antibiotic, anthelmintic, ectoparasiticidal, acaricidal or other pesticidal agents. However, there is still a continuing need to provide compounds with modified activity against one or more classes of parasites.